Process for preparing 3-alkoxy-5-alkypyrazin-2-amines

ABSTRACT

A process for preparing 3-alkoxy-5-alkylpyrazin-2-amines of the general formula: ##STR1## wherein R 1  is a C 1-4  -alkyl group or an aryl group and R 2  is a C 1-4  -alkoxy group or an aryloxy group, starting either from aminomalononitrile or from aminoacetonitrile.

This is a division of U.S. Ser. No. 08/889,435, filed on Jul. 8, 1997,now U.S. Pat. No. 5,877,319.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The invention relates to a novel process for preparing3-alkoxy-5-alkylpyrazin-2-amines starting either from aminomalononitrileor aminoacetonitrile and glyoxal oxime derivatives.

2. Background Art

3-Alkoxy-5-alkylpyrazin-2-amines are important intermediates forpreparing pterine-6-carboxyaldehyde [E. C. Taylor and D. G. Dumas, J.Org. Chem., (1980), p. 2485].

British Patent No. 922,725 describes a process for preparing3-methoxy-5-methylpyrazin-2-amine starting from2-amino-3-chloro-5-methylpyrazine by reaction with sodium methoxide at130° C. A disadvantage of this process is the relatively long reactiontime.

BROAD DESCRIPTION OF THE INVENTION

An object of the present invention is to provide an economical processfor preparing 3-alkoxy-5-alkylpyrazin-2-amines in good yield. Otherobjects and advantages of the invention are set out herein or areobvious herefrom to one skilled in the art.

The objects and advantages of the invention are achieved by the processand compounds of the invention.

According to the invention, the first step of the invention process iscarried out by converting aminomalononitrile, or its salt, of theformula: ##STR2## with a glyoxal oxime derivative of the generalformula: ##STR3## in a manner known per se according to the method ofTaylor et al. [J. Am. Chem. Soc., 95, (10), (1973), 6413-6418] into anoxypyrazinecarbonitrile of the general formula: ##STR4##

The two reactants, the aminomalononitrile and the glyoxal oximederivatives, are commercially available compounds. Aminomalononitriletosylate is an example of an aminomalononitrile salt which can be used.

The radical R¹ represents C₁₋₄ -alkyl or aryl. Suitable C₁₋₄ -alkylsinclude, for example, methyl, ethyl, propyl, butyl, isobutyl ortert-butyl. Suitable aryls include phenyl and benzyl with or withoutsubstitution.

The reaction of the first step is advantageously carried out in a polarsolvent. Suitable polar solvents include water, lower carboxylic acids,lower alcohols, nitriles such as acetonitrile, dimethylformamide,dimethylacetamide and dimethyl sulfoxide. Suitable lower alcoholsinclude methanol, ethanol, propanol, isopropanol, butanol, isobutanoland tert-butanol. Suitable lower carboxylic acids include formic acid,acetic acid, propionic acid and butyric acid.

The reaction of first step is advantageously carried out under an inertgas atmosphere and at a temperature of from 0° to 180° C., preferablyfrom 10° to 30° C.

In the second step, the oxypyrazinecarbonitrile derivative (formula IV)is hydrolyzed to give an oxypyrazinecarboxylic acid of the generalformula: ##STR5##

In the oxypyrazinecarboxylic acid salt, M represents a metal atom, forexample, an alkali metal atom or an alkaline earth metal atom, orammonium. In particular, M represents an alkali metal atom.

The hydrolysis is advantageously carried out in aqueous media and in thepresence of a base or an acid. Suitable bases include alkali metalhydroxides, alkaline earth metal hydroxides or ammonium salts. Suitablealkali metal hydroxides include sodium hydroxide and potassiumhydroxide. Suitable alkaline earth metal hydroxides include calciumhydroxide and magnesium hydroxide. Suitable acids include sulfuric acidand hydrohalic acids such as HCl, HBr and HI. The hydrolysis ispreferably carried out in the presence of a base.

The hydrolysis is advantageously carried out under an inert gasatmosphere an d at a temperature from 0° to 100° C. The hydrolysis ispreferably carried out at a temperature from 50° to 80° C.

In the third step, the oxypyrazinecarboxylic acid salt (formula V) ishalogenated to give a halooxypyrazine of the general formula: ##STR6##

The substituent X represents a halogen atoms such as fluorine, chlorine,bromine or iodine. The halogenation may be carried out using a halogenor halooxy acids or salts thereof. Suitable halogens include Cl₂, Br₂and I₂ ; preference is given to Br₂. Suitable halooxy acids include thefollowing: HClO, HBrO, HIO, HClO₃, HBrO₃ and HIO₃, and alkali metalsalts thereof such as KOBr and NaBrO₃.

The halogenation of step three is advantageously carried out at atemperature of from -30° to 100° C., preferably at a temperature of from0° to 30° C.

Suitable solvents for the halogenation are polar solvents such as water,lower alcohols or aqueous lower alcohols. Suitable lower alcoholsinclude methanol, ethanol, propanol and butanol.

In the fourth step, the halooxypyrazinamine (formula VI) is convertedinto a 3-alkoxy-5-alkyl-1-oxypyrazin-2-ylamine of the general formula:##STR7## wherein R¹ is as defined above, and R² is a C₁₋₄ -alkoxy groupor an aryloxy group, using either an alcohol in the presence of a baseor an alkoxide.

Suitable C₁₋₄ -alkoxy groups include methoxy, ethoxy, propoxy,isopropoxy, butoxy, isobutoxy and tert-butoxy. Suitable aryloxy groupsinclude phenyloxy and benzyloxy with or without substitution.

The corresponding alkali metal C₁₋₄ -alkoxides or alkali metal arylalkoxides are advantageously employed as alkoxides. Suitable alkalimetal C₁₋₄ -alkoxides include sodium methoxide, potassium methoxide,sodium ethoxide, potassium ethoxide, sodium propoxide, potassiumpropoxide, sodium butoxide and potassium butoxide. Suitable alkali metalaryl alkoxides include sodium phenoxide, potassium phenoxide, sodiumbenzyl alkoxide and potassium benzyl alkoxide. The corresponding C₁₋₄-alcohols or aryl alcohols, for example, methanol, ethanol, propanol,isopropanol, butanol, tert-butanol, isobutanol, phenol or benzylalcohol, are advantageously employed as the alcohol. Suitable basesinclude the same bases as mentioned for step two.

In step four, the corresponding alcohol or the corresponding aqueousalcohol is usually employed as solvent.

The reaction of step four is advantageously carried out under an inertgas atmosphere and at a temperature of from 0° to 180° C., preferably ata temperature of from 20° to 80° C.

In step five, the 3-alkoxy-5-alkyl-1-oxypyrazin-2-ylamine (formula VII)is reduced to give the end product of general formula I.

The reduction of step five is advantageously carried out catalyticallyusing hydrogen, PCl₃ or Na₂ S₂ O₄, preferably catalytically usinghydrogen.

Suitable hydrogenation catalysts include noble metal, noble metal oxideand Raney catalysts, which if appropriate are deposited on a carrier.Examples of hydrogenation catalysts include Raney nickel, platinum oncarbon or platinum on aluminum oxide. It is advantageous to employplatinum on carbon, in particular 1 to 10 percent by weight of platinumon carbon, as the hydrogenation catalyst. The hydrogenation catalystscan be employed in amounts of from 0.1 to 40 percent by weight,preferably from 5 to 20 percent by weight, based on the3-alkoxy-5-alkyl-1-oxypyrazin-2-ylamine. The hydrogenation isadvantageously carried out at an elevated H₂ pressure, preferably at apressure from 1 to 10 bar.

The reduction of step five is advantageously carried out in a polarsolvent. Suitable polar solvents include, for example, lower alcohols,water, dimethylformamide and carboxylic acids. Suitable lower alcoholsare the same as mentioned for step three. Suitable carboxylic acidsinclude, for example, formic acid and acetic acid.

The reaction is advantageously carried out under an inert gas atmosphereand at a temperature of from 0° to 250° C., preferably of from 120° to180° C.

In a preferred embodiment, the entire process is carried out withoutisolation of the oxypyrazine-carboxylate salt (formula V).

In a further embodiment according to the invention, the first processstep is carried out in such a way that aminoacetonitrile or a saltthereof of the formula:

    H.sub.2 N--CH.sub.2 --CN                                   VIII

is converted with a glyoxal oxime derivative of the general formula:##STR8## wherein R¹ is as defined above, in the presence of a base in amanner known per se by the method of J. Heterocycl. Chem., (1985),1145-1146, into an oxypyrazinamine of the general formula: ##STR9##wherein R¹ is as defined above.

The reactant aminoacetonitrile is commercially available. Suitableaminoacetonitrile salts include its hydrochloride and hydrobromidesalts.

Suitable bases include methylmorpholine, triethylamine, pyridine, analkali metal hydroxide, an alkoxide or an alkali metal carbonate.Suitable alkoxides are the same as used in step four of the processvariant described above. Suitable alkali metal hydroxides are the sameas used in step two of the process variant described above. Suitablealkali metal carbonates include sodium carbonate and potassiumcarbonate.

According to this process variant, the reaction of step one isadvantageously carried out in a polar solvent. Suitable polar solventsinclude halogenated hydrocarbons, such as, dichloromethane, chloroform,carbon tetrachloride, trichioroethane, tetrachloroethane, ethylenechloride and (hydro)chlorofluorocarbons, the lower alcohols describedabove, the lower carboxylic acids described above, water,dimethylformamide and dimethylacetamide.

The reaction of step one is advantageously carried out under an inertgas atmosphere and at a temperature of from -30° to 100° C., preferablyof from 0° to 40° C.

In the second step of this process variant, the oxypyrazinamine (formulaIX) is halogenated to give a halooxypyrazinamine of the general##STR10## wherein R¹ and X are each as defined above.

Suitable halogenating reagents and suitable solvents for thehalogenation include those used in the variant described above.

According to this variant, the halogenation is advantageously carriedout at a temperature of from -30° to 100° C., preferably at atemperature of from 0° to 30° C.

The other reaction steps of this process variant are carried outsimilarly to the variant described above, i.e., the third step of thisvariant is carried out similarly to the fourth step of the variantdescribed above and the fourth step of this variant is carried outsimilarly to the fifth step of the variant described above.

This process variant is advantageously carried out without isolation ofthe intermediate of the formula VI.

The oxypyrazinecarboxylic acid salts (formula V), thehalooxypyrazinamines (formula VI) and the3-alkoxy-5-alkyl-1-oxypyrazin-2-ylamine (formula VII) have not beendescribed in the literature and, thus, as novel intermediates forpreparing 3-alkoxy-5-alkylpyrazin-2-amines, form part of the subjectmatter of the invention.

M in the oxypyrazinecarboxylic acid salt advantageously represents analkali metal atom such as sodium or potassium.

The substituent X in the halooxypyrazinamine (formula VI) is as definedabove and advantageously represents bromine.

The radical R¹ in the halooxypyrazinamine (formula VI) and in the3-alkoxy-5-alkyl-1-oxypyrazin-2-ylamine (formula VII) is as definedabove and advantageously represents C₁₋₄ -alkyl, preferably methyl. Inthe 3-alkoxy-5-alkyl-1-oxypyrazin-2-ylamine (formula VII), R² is asdefined above and advantageously represents C₁₋₄ -alkoxy, preferablymethoxy.

Thus, the most preferred compounds are3-bromo-5-methyl-1-oxypyrazin-2-ylamine (formula VI) and3-methoxy-5-methyl-1-oxypyrazin-2-ylamine (formula VII).

DETAILED DESCRIPTION OF THE INVENTION EXAMPLE 1

Preparation of 3-amino-6-methyl-4-oxypyrazine-2-carbonitrile

34.80 g of anti-methylglyoxal 1-oxime (391.6 mmol) and 98.15 g ofaminomalononitrile toluene-4-sulfonate (379 mmol) were charged initiallywith 600 ml of isopropanol into a 1000 ml flask under argon, and stirredat 20° C. for 4 hours. After cooling to 5° C., the product was filteredand washed with 40 ml of cold water and 40 ml of cold ethanol. Afterdrying, a crude product (55.28 g) was obtained. The crude product wasstirred for 30 minutes at 85° C. in 150 ml of ethanol (slurry). Theproduct was filtered at 14° C. and dried. 53.35 g of3-amino-6-methyl-4-oxypyrazine-2-carbonitrile was obtained. The yield ofthe product was 91.3 percent. Other data concerning the product was:

¹ H NMR (DMSO-d₆, 400 MHz)δ:

2.29 (s, 3H);

7.70 (s, 2H);

8.45 (s, 1H).

Melting point: 187°-188° C.

EXAMPLE 2

Preparation of 3-amino-6-phenyl-4-oxypyrazine-2-carbonitrile

25.1 g of isonitrosoacetophenone (167.4 mmol) and 41.9 g ofaminomalononitrile toluene-4-solfonate (162.1 mmol) were chargedinitially with 250 ml of isopropanol into a 500 ml flask under argon,and stirred at 20° C. for 4 hours. After cooling to 5° C., the productwas filtered and washed with 40 ml of cold water and 40 ml of coldethanol. After drying, a crude product (33.12 g) was obtained. The crudeproduct was three times slurried up in 100 ml of water at 20° C. andthen filtered. 11 g of 3-amino-6-phenyl-4-oxypyrazine-2-carbonitrile wasobtained. The yield of the product was 32 percent. Other data concerningthe product was:

¹ H NMR (DMSO-d₆, 400 MHz)δ:

7.45 (m, 3H);

7.97 (m, 2H);

8.05 (s, 2H);

9.18 (s, 1H).

¹³ C NMR (DMSO-d₆, 400 MHz)δ:

149.519

142.298

134.147

131.306

129.286

128.797

125.609

115.106

11.184

EXAMPLE 3

Preparation of 3-bromo-5-methyl-1-oxopyrazin-2-ylamine without isolationof intermediate (formula V)

3-Amino-6-methyl-4-oxopyrazine-2-carbonitrile (10.04 g; 66.8 mmol), KOH(5.23 g, 85 percent pure) (86.3 mmol) and water (66 g) were chargedinitially in a 250 ml flask under argon and heated to 45° C. for 3hours. 10.6 g of bromine (66.3 mmol) was then added dropwise over 30minutes at 18° C. (exothermic reaction and gas formation). Thetemperature increased to 28° C. The mixture was stirred at 20° C. for 1hour, and 40 ml of n-butanol was added for the extraction. After thephase separation, the mixture was twice extracted with 30 ml ofn-butanol each time. The organic phase was concentrated completely.After drying, 9.4 g of 3-bromo-5-methyl-1-oxopyrazin-2-ylamine wasobtained. The yield of the product was 68 percent. Other data concerningthe product was:

¹ H NMR (DMSO-d₆, 400 MHz)δ:

2.15 (s, 3H);

6.90 (s, 2H);

8.18 (s, 1H).

EXAMPLE 4

Preparation of 3-methoxy-5-methyl-1-oxypyrazin-2-ylamine

(a) Under argon, the 3-bromo-5-methyl-1-oxopyrazin-2-ylamine (3.57 g;16.8 mmol) and methanol (50 ml) were charged initially. At 20° C., asolution of sodium methoxide (3.47 g; 19.2 mmol) was added dropwise over15 minutes. The mixture was stirred at 62° C. for 2 hours. The solventwas completely removed by distillation. According to NMR analysis,3-methoxy-5-methyl-1-oxypyrazin-2-ylamine was obtained. The yield of theproduct was 90 percent.

(b) Under argon, 3-bromo-5-methyl-1-oxopyrazin-2-ylamine (4.2 g; 20mmol), methanol (22.5 g), water (21.2 g) and KOH (1.4 g; 21.2 mmol) werecharged initially in a flask. At 70° C., the mixture was stirred for 3.5hours. The methanol was distilled off and the product was three timesextracted with 20 ml of n-butanol each time. 3.07 g of3-methoxy-5-methyl-1-oxypyrazin-2-ylamine was obtained. The yield of theproduct was 99 percent. Other data concerning the product was:

¹ H NMR (DMSO-d₆, 400 MHz)δ:

2.10 (s, 3H);

3.96 (s, 3H);

6.50 (s, 2H);

7.66 (s, 1H).

EXAMPLE 5

Preparation of 3-methoxy-5-methylpyrazin-2-amine

3-Methoxy-5-methyl-1-oxopyrazin-2-ylamine (1 g; 6.44 mmol) and methanol(50 ml) were charged initially together with 0.19 g of Pt/C-5 percentinto an autoclave. The autoclave was first flushed with argon (threetimes), and a hydrogen pressure of 10 bar was then applied. Thehydrogenation proceeded for 5 hours at 130° C. At 20° C., the autoclavewas flushed with argon. The catalyst was filtered and washed with 5 mlof methanol. The solvent was completely removed by distillation. 0.85 gof 3-methoxy-5-methylpyrazin-2-amine was obtained. The yield of theproduct was 95 percent. Other data concerning the product was:

¹ H NMR (DMSO-d₆, 400 MHz)δ:

2.20 (s, 3H);

3.87 (s, 3H);

5.90 (s, 2H);

7.33 (s, 1H).

Melting point: 75°-76.5° C.

EXAMPLE 6

Preparation of 5-methyl-1-oxypyrazin-2-amine

Isonitrosoacetone (18.7 g; 0.21 mol) and methylmorpholine (22.0 g; 0.213mol) were charged initially with chloroform (200 ml) into a flask underargon. At 65° C., aminoacetonitrile hydrochloride (24.35 g; 0.257 mol)was added a little at a time over 2 hours, and stirring was continuedfor a further 2 hours at this temperature. At 20° C., water (80 ml) andHCl (32 percent strength; 12.9 g) were then added. The crude solutionwas filtered through celite and the phases were then separated. Theaqueous phase was adjusted to pH 11 using NaOH (30 percent strength;71.0 g). The product was extracted with 2-methyl-2-butanol (4 times 60ml each time) at 40° C. The organic phase was completely removed bydistillation. 7.68 g of the product, corresponding to a yield of 30percent, was obtained. Other data concerning the product was:

NMR (DMSO-d₆) (400 MHz):

2.24 (s, 3H);

6.70 (s, 2H);

8.02 (s, 2H).

EXAMPLE 7

Preparation of 3-methoxy-5-methyl-1-oxypyrazin-2-ylamine (withoutisolation of 3-bromo-5-methyl-1-oxypyrazin-2-ylamine)

(a) 5-methyl-1-oxypyrazin-2-amine (2.0 g; 15.9 mmol), KOH (85 percentpure; 1.21 g; 18.3 mmol), water (6 g) and methanol (9.5 g) wereinitially charged in a flask under argon. At 3° C., bromine (4.92 g;30.7 mmol) was then added dropwise over 30 minutes. The temperatureincreased to 10° C. The mixture was stirred at 20° C. for 1 hour, andKOH (64 mmol) and methanol (7.9 g) were added. The mixture was thenstirred at 72° C. for 2 hours. The methanol was distilled off and theproduct was extracted with 2-methyl-2-butanol (3 times 40 ml each time).The organic phase was concentrated completely After drying, 1.58 g ofthe product, corresponding to a yield of 63 percent, was obtained. Otherdata concerning the product was:

NMR (DMSO-d₆) (400 MHz):

2. 10 (s, 3 H);

3.96 (s, 3H);

6.50 (s, 2H);

7.66 (s, 1 H).

(b) The 3-amino-6-methyl-4-oxopyrazine-2-carbonitrile (20 g; 129.8mmol), KOH (1 3.36 g; 85 percent pure) (203.9 mmol) and water (130 g)were charged initially in a flask under argon and heated to 45° C. for 3hours. At 9° C., 33.58 g of bromine (210 mmol) and 25 g of methanol werethen added dropwise over 30 minutes (exothermic reaction and formationof gas). The temperature increased to 13° C. The mixture was stirred at20° C. for 1 hour, and 19.14 g of KOH (290 mmol) and 63 g of methanolwere added. The mixture was stirred at 72° C. for 2 hours. The methanolwas distilled off and the product was extracted continuously with2-methyl-2-butanol. The 3-methoxy-5-methyl-1-oxopyrazin-2-ylamineprecipitated in 2-methyl-2-butanol. After filtration at 5° C. anddrying, 21.05 g of 3-methoxy-5-methyl-1-oxopyrazin-2-ylamine wasobtained. The yield of the product was 82 percent.

What is claimed is:
 1. A process for preparing a3-alk(ar)oxy-5-alkyl(aryl)pyrazin-2-amine of formula: ##STR11## whereinR¹ represents a C₁₋₄ -alkyl group or an aryl group and R² represents aC₁₋₄ -alkoxy group, a phenoxy group or an arylalkoxy group, comprisingin a first step, reacting aminoacetonitrile, or a salt thereof, offormula:

    H.sub.2 N--CH.sub.2 --CN                                   VIII

with a glyoxal oxime derivative of formula: ##STR12## wherein R¹ is asdefined above, in the presence of a base (a) to provide anoxypyrazinamine of formula: ##STR13## wherein R¹ is as defined above, ina second step, halogenating the oxypyrazinamine of formula IX to give ahalooxypyrazinamine of formula: ##STR14## wherein R¹ is as definedabove, and X is a halogen atom, in a third step, reacting thehalooxypyrazinamine of formula VI with an alcohol in the presence of abase (b) or with an alkoxide, phenoxide or an aryl alkoxide to provide a3-alk(ar)oxy-5-alkyl(aryl)-1-oxypyrazin-2-ylamine of formula: ##STR15##wherein R¹ and R² are each as defined above, and in a fourth step,reducing the 3-alk(ar)oxy-5-alkyl(aryl)-1-oxypyrazin-2-ylamine offormula VII to give the end product of formula I.
 2. The processaccording to claim 1, wherein the reaction in the third step is carriedout without isolation of the intermediate of the formula VI.
 3. Theprocess as claimed in claim 1 wherein, in the first step, base (a) ismethylmorpholine, triethylamine, pyridine, an alkali metal hydroxide, analkoxide or an alkali metal carbonate.
 4. The process as claimed inclaim 1 wherein, in the first step, the salt of the aminoacetonitrile isthe hydrochloride or the hydrobromide.
 5. The process as claimed inclaim 1 wherein, in the first step, the reaction is conducted in a polarsolvent.
 6. The process as claimed in claim 5 wherein the polar solventis a halogenated hydrocarbon, a lower alcohol, a lower carboxylic acid,water, dimethylformamide or dimethylacetamide.
 7. The process as claimedin claim 1 wherein, in the second step, the halogenating agent is ahalogen, a halooxy acid or a salt of a halooxy acid.
 8. The process asclaimed in claim 7 wherein the halogenating agent is Cl₂, Br₂, I₂, HClO,HBrO, HIO, HClO₃, HBrO₃, HIO₃, KOBr or NaBrO₃.
 9. The process as claimedin claim 1 wherein in the second step, the halogenation is conducted ina polar solvent.
 10. The process as claimed in claim 9 wherein the polarsolvent is water, a lower alcohol or an aqueous lower alcohol.
 11. Theprocess according to claim 1, wherein the base (b) used in the thirdstep is an alkali metal hydroxide, an alkaline earth metal hydroxide ora basic ammonium salt.
 12. The process according to claim 1 wherein thethird step is conducted in the presence of an alkoxide or an arylalkoxide.
 13. The process according to claim 12 wherein the alkoxideused in the third is an alkali metal C₁₋₄ -alkoxide or an alkali metalaryl-alkoxide.
 14. The process according to claim 12 wherein thereduction of the fourth step is carried out catalytically with hydrogen,PCl₃ or Na₂ S₂ O₄.
 15. The process according to claim 14, wherein ahydrogenation catalyst which is platinum on carbon is used in the fourthstep.
 16. The process according to claim 1 wherein the reduction of thefourth step is carried out catalytically with hydrogen, PCl₃ or Na₂ S₂O₄.
 17. The process according to claim 1, wherein a hydrogenationcatalyst which is platinum on carbon is used in the fourth step.